Borylation of primary and secondary alkyl bromides catalyzed by Cu₂O nanoparticles

Abstract

A Cu₂O nanoparticle catalyzed borylation of activated and unactivated alkyl bromides is developed, using bis(pinacolato)diboron as a boron source. To the best of our knowledge this is the first report of a heterogeneous Cu₂O nanocatalyst applied in the direct synthesis of primary and secondary alkylboronic esters. Our catalytic system features mild reaction conditions, high yield (nearly 100%) and the absence of ligands which otherwise are essential in homogenous catalysis.

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Alkylboron compounds are an important synthetic intermediate in medicinal chemistry due to their wide application in Suzuki–Miyaura cross-coupling reactions.¹ Traditionally, alkylboron compounds are synthesized via borylation of alkyllithium or alkylmagnesium reagents with suitable boron compounds.² These procedures suffer from low shelf stability and poor compatibility with limited functional groups.³ In order to develop more practical synthetic routes, several protocols with transition metal based homogenous catalysts have been studied lately, including Rh- and Ir-catalyzed olefin hydroboration,⁴ Ru-, Rh-, Ir- and Re-catalyzed alkane C–H borylation,⁵ as well as Pd-, Ni-, Fe, Cu- and so on catalyzed β-borylation of unsaturated carbonyl compounds.^6–8 Very recently, researchers successfully developed a new approach utilizing alkyl halides or pseudohalides as substrates. Liu and co-workers have shown that Cu(I) and Pd₂(dba)₃ could both catalyze the borylation of alkyl halides (Scheme 1a and c).⁹ Cu NPs exhibit good catalytic activity in this reaction (Scheme 1b).⁹ Tertiary alkyl electrophiles were first achieved by Fu and co-workers (Scheme 1d).⁹ Although this method is proved efficient, there are also disadvantages: the catalyst input dosage is relatively high; complicated experimental setup or expensive ligand is required.

Scheme 1 Synthetic methods of alkylboronic esters from alkyl halides.

In our previous work, we found Cu(I) nanoparticles have high catalytic activity in hydroxylation, amination, and thiolation of aryl halides. The reaction condition is environmentally benign without ligand presence.¹⁰ It would be interesting to explore the catalytic performance of nanoparticle in direct borylation of alkyl halides. Herein, we report a nanostructure Cu₂O catalyst for the synthesis of activated or unactivated primary and secondary alkylboron compounds through borylation of the corresponding alkyl bromides. Our results demonstrate that it is effective in terms of reaction yield with wide applicability for various alkyl functional groups, and does not require ligand. To our best knowledge, it is the first Cu₂O nanocatalyst documented, in comparison to other homogenous catalysts for this reaction (Scheme 1).

We chose 1-bromo-2-phenylethane (1a) as a model substrate and bis(pinacolato)diboron (B₂pin₂) as a diboron reagent. Cu(I) (10 mol%) was used as a starting catalyst. Limited product (4%) was found under ligand-free condition, with dimethylformamide (DMF) as a solvent (Table 1, entry 1).⁹ We then used bulk Cu₂O (10 mol%) in the reaction system (Table 1, entry 2), and small amount of desired product (12%) was detected. It inspired us to study further on the activity of Cu₂O nanoparticles (NPs) prepared according to literature.¹¹ Carbon black (CB) was used as a support material, in order to prevent nanoparticles aggregation.¹² Control experiment confirmed that no conversion occurred with only CB (Table 1, entry 3). When Cu₂O NPs/CB (0.8 mol% Cu₂O)¹³ was used as a catalyst, the yield of product improved significantly to 56% (Table 1, entry 4), indicating this nanocatalyst substantially exhibits better catalytic activity. Further, we tuned different experimental parameters to maximize catalytic efficiency. The solvent was changed to tetrahydrofuran (THF), methanol (MeOH), ethanol (EtOH) and tert-butyl alcohol (t-BuOH). Highest yield (97%) was obtained in EtOH trial (Table 1, entries 5–8). In terms of base effect, we learnt sodium hydroxide (NaOH), sodium tert-butoxide (t-BuONa), potassium carbonate (K₂CO₃) and potassium phosphate (K₃PO₄) were inferior to lithium methoxide (LiOMe) (Table 1, entries 9–12). The optimal reaction time was proved to be 12 h (Table 1, entries 13–14). Additionally, lower yields were obtained when the amount of base or Cu₂O nanoparticles was reduced (Table 1, entries 15–16), indicating conversion rate is proportional to both base concentration and catalyst dosage. Since CuO may grow when Cu₂O nanoparticles are exposed in air, we also examined the catalytic effect of pure CuO nanoparticles, which shows no catalytic activity (Table 1, entry 17). To quantitatively assess the air influence particularly during batch processing, we tested our catalytic reaction in air without argon protection, which indeed gave negative impact (yield drops to 56%) (Table 1, entry 18). Lastly, we discovered this catalysis system was fairly insensitive to moisture, because adding 4 equivalents of water only reduces the yield to 95% (Table 1, entry 19).

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst	Base	Solvent	Time (h)	Yield^b [%]
a Reaction conditions: 1-bromo-2-phenylethane (0.25 mmol), B2Pin2 (0.375 mmol), base (0.5 mmol), Cu2O NPs/CB (0.8 mol% Cu2O) under Ar.b GC yield using biphenyl as an internal standard.c With 1 equiv. base.d With 3 mg Cu2O NPs/CB.e In air.f 4.0 equiv. of H2O was added.
1	Cu(I)	LiOMe	DMF	24	4
2	Cu2O	LiOMe	DMF	18	12
3	CB	LiOMe	DMF	18	NR
4	Cu2O NPs/CB	LiOMe	DMF	18	56
5	Cu2O NPs/CB	LiOMe	THF	18	42
6	Cu2O NPs/CB	LiOMe	MeOH	18	78
7	Cu2O NPs/CB	LiOMe	EtOH	18	97
8	Cu2O NPs/CB	LiOMe	t-BuOH	18	51
9	Cu2O NPs/CB	NaOH	EtOH	18	65
10	Cu2O NPs/CB	t-BuONa	EtOH	18	88
11	Cu2O NPs/CB	K2CO3	EtOH	18	11
12	Cu2O NPs/CB	K3PO4	EtOH	18	14
13	Cu2O NPs/CB	LiOMe	EtOH	12	97
14	Cu2O NPs/CB	LiOMe	EtOH	8	89
15^c	Cu2O NPs/CB	LiOMe	EtOH	12	60
16^d	Cu2O NPs/CB	LiOMe	EtOH	12	58
17	CuO NPs/CB	LiOMe	EtOH	12	NR
18^e	Cu2O NPs/CB	LiOMe	EtOH	12	56
19^f	Cu2O NPs/CB	LiOMe	EtOH	12	95

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In view of this efficient catalytic system in hand, we next extended the scope of the substrate to various primary alkyl bromides (Scheme 2). The isolated yield of 3a is 92%. Linear chain or branched chain alkyl bromides give high yield (3b, 3c, 3d, 3e). Alkyl iodide (3f) gives a higher conversion rate while alkyl chloride do not react at all. This reactivity distinction can be used to selectively borylate the C–Br bond when C–Cl (3g) bond coexist in the reaction system. Other useful functional groups such as ester (3h), ketal (3i), ether (3j) and cyano (3k) groups are well tolerated in the current catalytic system, since isolated yields of desired alkylboronates range from 50% to 92%. Benzyl bromide (3l) as a reactive electrophile which can be hardly borylated starting from alkyllithium or alkylmagnesium reagents, gives 54% yield in our catalytic reaction. In further studies, we found if aryl bromide and alkyl bromide were both present in the substrate (3m), only alkyl bromide could be borylated (52%), while aryl bromide does not react simultaneously. It reveals that aryl halides group in the substrate is stable during the reaction. When two bromines are contained in the substrate (3n), both of them can be borylated with 3.0 equivalents of B₂pin₂.

Scheme 2 Substrate scope of the borylation reaction of primary alkyl bromides. Reaction conditions: alkyl bromide (0.25 mmol), B₂Pin₂ (0.375 mmol), MeOLi (0.5 mmol), EtOH (1.5 mL), and Cu₂O NPs/CB (0.8 mol% Cu₂O) at room temperature under Ar atmosphere for 12 h. All yields are Isolated yields. ^a1e is 1-iodopentane. ^bB₂Pin₂ (0.75 mmol).

In addition to primary alkyl borylation, secondary and tertiary alkyl group borylation is an emerging research focus in this field. In Pd based catalysis systems, secondary alkyl bromide cannot be borylated.⁹ Nonetheless, Cu based catalysts helps borylate primary electrophile, but secondary and tertiary electrophiles have seldom been active.^9,14,15 Therefore, we also would like to examine the effect of the catalyst on secondary and tertiary electrophiles (Scheme 3). Cyclic secondary alkyl bromides with different ring sizes (5a–5d) can be successfully borylated: cycloheptyl bromide yields 71%, cyclohexyl 68%, cyclopentyl 75% and cyclobutyl 50%, respectively. Other substrates, such as bicyclic (5e, 5f) and acyclic (5g) bromides can also be converted. When functional group such as cyano (5h) exists in the substrate, high yield can be obtained (85%). Still, tertiary electrophiles were unsuccessful (not shown in Scheme 3).

Scheme 3 Substrate scope of the borylation reaction of secondary alkyl bromides. Reaction conditions: alkyl bromide (0.25 mmol), B₂Pin₂ (0.375 mmol), MeOLi (0.5 mmol), EtOH (1.5 mL), and Cu₂O NPs/CB (0.8 mol% Cu₂O) at room temperature under Ar atmosphere for 12 h. All yields are isolated yields.

Furthermore, other diboron reagents were used in our reaction system to evaluate the tolerance of our Cu₂O nanocatalyst under different boron sources. We found in the presence of bis(neopentylgly-colato)diboron (B₂(neop)₂), primary alkyl (7a), secondary alkyl (7b) and secondary alkyl with cyano group (7c) substrates can be catalyzed successfully, although yields of these reactions were lower than those of the corresponding pinacol alkylboronate esters (Scheme 4).

Scheme 4 Borylation of Alkyl Bromides Using Bis(neopentylgly-colato)diboron. Alkyl bromide (0.25 mmol), B₂(neop)₂ (0.375 mmol), MeOLi (0.5 mmol), EtOH (1.5 mL), and Cu₂O NPs/CB (0.8 mol% Cu₂O) at room temperature under Ar atmosphere for 12 h. All yields are isolated yields.

Activity and reusability are also key factors to test catalyst feasibility in real industry application. To this point, a gram-scale reaction was attempted. In the presence of Cu₂O NPs/CB (0.8 mol%), 1a reacts with B₂pin₂ at room temperature for 12 h to produce 3a in 90% yield (Table 2). This proves our nanocatalyst has potential for industry process. As well, the catalyst is recovered from the reaction mixture by centrifugation and reused for the fresh reaction.¹⁶ Only a slight decrease in catalytic activity after three cycles (81% of third cycle vs. 90% of first cycle) is observed, which demonstrates an excellent recyclability.

Table 2 Gram-scale reaction and recyclability of Cu₂O NPs/CB^a

Run	Catalyst recovery (%)	Product yield^b (%)
a Reaction conditions: alkyl bromide (10 mmol), B2Pin2 (15 mmol), MeOLi (20 mmol), EtOH (15 mL), and Cu2O NPs/CB (0.8 mol% Cu2O) at room temperature under Ar atmosphere for 12 h.b All yields are isolated yields.
1	92	90
2	90	88
3	84	81

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Finally, the Cu₂O NPs/CB catalyst was characterized by different techniques. Fig. 1a shows transmission electron microscopy (TEM) image of an as-obtained sample. It suggests Cu₂O nanoparticles with average diameter of 137.5 nm (Fig. 1b). The X-ray photoelectron spectroscopy (XPS) spectrum in Fig. 1c is performed to detect the valence of catalysts. 932.7 eV peak was assigned for Cu(I) 2P_3/2, 952.4 eV peak for Cu(I) 2P_1/2. But the satellite shakeup feature characteristic of Cu(II) species were observed and two additional peaks at 934.0 eV and 953.8 eV could be indexed to Cu(II) 2p_3/2 and Cu(II) 2p_1/2 of CuO, respectively. It is possible attributed to partial oxidation of Cu₂O to CuO. The X-ray diffraction (XRD) pattern is shown in Fig. 1d. The diffraction peak of 2θ = 25° can be assigned to CB. All other diffraction peaks could be perfectly indexed to Cu₂O (JCPDS, no. 78-2076). The recovered catalyst was characterized by TEM and XRD (Fig. 1e and f). It can be seen from TEM image that most nanoparticles still maintain integrity. The average size increases a bit, probably due to Ostwald ripening effect during catalytic process. The XRD pattern shows a new peak around 39° between Cu₂O (111) and (200) peaks after recovering. It is highly possible the CuO (111) peak, which is consistent with our rationale from XPS result. A Cu content of 5.0 wt% in the catalyst was determined by atomic absorption spectroscopy (AAS).

Fig. 1 (a) TEM before the reaction, (b) the size distribution of Cu₂O NPs, (c) XPS, (d) XRD before the reaction, (e) TEM after third cycle, (f) XRD after third cycle.

In conclusion, we have developed an efficient route for the borylation of primary and secondary alkyl bromides catalyzed by Cu₂O nanoparticles. Our approach gives high yield of borylation of primary and secondary alkyls with wide range of functional groups, with either B₂pin₂ or B₂(neop)₂ as boron donor. It also demonstrates outstanding recyclability and hence has enormous potential in large-scale production.

Notes and references

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12. The nanoparticles can be dispersed in a liquid, but it will become an obstacle in the optimization of solvent. The nanoparticles are easy to agglomerate, if separated from the liquid. The required amount of catalyst is very little, it is difficult to precisely control. When the catalyst is supported on a carrier, aggregation can be prevented, and it is easy to weigh the catalyst.
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16. After the reaction, the catalyst was recovered by centrifugation. The collected catalyst was rinsed with ethanol and H₂O for three times, then dried in vacuo. At last, the recovered catalyst was weighed and used for a fresh reaction.

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Footnote

† Electronic supplementary information (ESI) available: Optimization of the reaction conditions, synthetic procedures for the catalysts, characterization data and copies of spectra. See DOI: 10.1039/c5ra06631j

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